The role of ARID1A in endometriosis-related infertility

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ABSTRACT Endometriosis occurs when endometrial tissue grows outside the uterine cavity, and this painful disease afflicts about 10% of reproductive-aged women. Up to 50% of these women also experience infertility, and many cases cannot be explained by morphological or ovarian defects, which implicates a uterine environment non- receptive to embryo implantation. The molecular basis for the correlation of endometriosis and uterine non- receptivity is unclear, but it likely involves signaling downstream of the steroid hormones progesterone and estrogen in the endometrium. Progesterone and estrogen signaling must be tightly regulated for the successful establishment and maintenance of pregnancy but they imbalanced in endometriosis, leading to progesterone resistance and estrogen dominance. ARID1A, a chromatin remodeling factor, is directly associated with progesterone signaling through the progesterone receptor and is remarkably reduced in the endometrium of infertile women with endometriosis. ARID1A is necessary for fertility in mice due to its role supporting implantation, decidualization, and endometrial receptivity. Uterine loss of ARID1A results in aberrant epithelial proliferation characteristic of progesterone resistance in women with endometriosis. We hypothesize that ARID1A loss provides the molecular key to endometriosis-related infertility by causing increased endometriotic lesion development and decreased endometrial receptivity based on its role regulating steroid hormone signaling. We will address the complex problem of endometriosis-related infertility by examining the causal link between ARID1A loss in endometriotic lesions and the development of endometriosis-related infertility (Aim 1) as well as the endometrial compartment-specific role of ARID1A loss in the dysregulation of steroid hormone signaling observed in the eutopic endometrium of women endometriosis (Aim 2). Our innovative endometriosis model mice, uterine Arid1a knockout mice, and tissue samples from infertile women with endometriosis will be powerful tools to analyze ARID1A's role in the pathophysiology of endometriosis-related infertility and the dysregulated molecular mechanisms of steroid hormone signaling in the endometriosis-affected uterus.